Potassium Phosphate, Tribasic → (2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate

HRID 718376Notes

Reaction equation

HRID 718376 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:29][CH2:28]3)[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:30][C:31]1[CH:48]=[CH:47][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:48][CH:47]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 118307883(2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateHCID 123643410(4-(4-Fluorophenethoxy)phenyl)boronic acid

Product 1

HCID 118307877(2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 49.6%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

The Pd(Ph3P)4 (61.8 mg, 0.053 mmol) was added to a nitrogen purged and degassed solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (125 mg, 0.27 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (77 mg, 0.29 mmol), and potassium phosphate tribasic (397 mg, 1.9 mmol) in 1,4-dioxane (3.5 mL) and water (0.9 mL). The reaction mixture was stirred in a screw-capped pressure vessel for 4 h at 90° C., cooled, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2CO3). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 80 mg (49.6%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.21-7.20 (m, 1H), 7.15-7.12 (m, 2H), 7.03-6.94 (m, 3H), 5.77/5.75 (s, 1H), 4.96-4.91 (m, 1H), 4.21 (t, J=6.6 Hz, 2H) 3.17-3.13/3.01-2.97 (m, 1H), 3.05 (t, J=6.6 Hz, 2H), 2.84-2.74 (m, 2H), 2.70-2.67/2.63-2.60 (m, 1H), 2.42/2.41 (s, 3H), 2.07/2.05 (s, 3H), 1.71-1.64 (m, 1H), 1.42-1.22/1.03-0.097 (m, 2H), 1.19-1.17 (m, 3H), 1.14-1.10 (m, 12H), 0.52-0.47 (m, 1H), 0.32-0.23 (m, 2H), −0.30-0.15 (m, 2H). UPLC (M+H)=603.5.

Workup

  1. custompurged
  2. temperaturecooled
  3. washthe organic layer was washed with brine
  4. dry with materialdried (Na2CO3)
  5. additionThe crude product was charged (DCM)
  6. washto a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes)

Sources & evidence

ORD record
ord-0b706898a4b04d7ea7a694ece6ff2e61
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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